This phase I/II trial studies the side effects and best dose of filgrastim (granulocyte colony-stimulating factor \[G-CSF\]), cladribine, cytarabine, and mitoxantrone, when given together with sorafenib and to see how well they work in treating patients with newly-diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome (likely to be more aggressive). Drugs used in chemotherapy, such as cladribine, cytarabine, and mitoxantrone work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Colony-stimulating factors, such as filgrastim, may increase the production of blood cells and may help the immune system recover from the side effects of chemotherapy. Sorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving filgrastim, cladribine, cytarabine, and mitoxantrone together with sorafenib may kill more cancer cells.
OUTLINE: This is a phase I, dose-escalation study of mitoxantrone and sorafenib followed by a phase II study. INDUCTION: Patients receive mitoxantrone intravenously (IV) over 60 minutes on days 1-3 and sorafenib orally (PO) twice daily (BID) on days 10-19 in the absence of disease progression or unacceptable toxicity. Patients also receive filgrastim subcutaneously (SC) once daily (QD) on days 0-5, cladribine IV QD over 2 hours on days 1-5, and cytarabine IV QD over 2 hours on days 1-5 in the absence of disease progression or unacceptable toxicity. Patients achieving partial remission (including MRD positive \[pos\] CR, CR with incomplete platelet recovery \[CRp\], and CR with incomplete count recovery \[CRi\]) or persistent AML may receive up to 2 cycles of induction therapy per the discretion of the treating physician. POST-REMISSION: Patients receive sorafenib PO BID on days 8-27 or 3 days prior to next cycle of treatment, whichever occurs first. Patients also receive filgrastim subcutaneously SC QD on days 0-5, cladribine IV QD over 2 hours on days 1-5, and cytarabine IV QD over 2 hours on days 1-5 in the absence of disease progression or unacceptable toxicity. Patients achieving MRDneg CR may receive up to 4 cycles of post-remission therapy. Patients achieving disease response (MRDpos CR, CRi/CRp, or persistent disease) may receive up to two induction cycles and 1 cycle of post-remission therapy with mitoxantrone omitted in cycle 3. If they then enter MRDneg CR, they can proceed with up to a total of 4 cycles of post-remission therapy. MAINTENANCE THERAPY: Patients achieving MRDneg CR may receive maintenance therapy of sorafenib PO BID for up to 1 year. After completion of study treatment, patients are followed up every 3 months for up to 5 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
84
Given IV
Given IV
Given SC
Correlative studies
Ancillary studies
Given IV
Given PO
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States
Phase 1: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of Mitoxantrone
MTD/RP2D will be defined as the highest dose studied in which the incidence of dose-limiting toxicity (DLT) is \< 33% assuming at least 6 patients have been treated at this dose. DLTs were defined as: 1) grade ≥3 non-hematologic toxicity lasting \>48 hours leading to \>7-day delay of the next cycle; 2) grade ≥4 non-hematologic toxicity if no recovery to grade ≤2 in 14 days (both excluding febrile neutropenia/ infection); 3) Absolute neutrophil count \<500/ µL or platelet count \<50,000/µL for \>49 days after CLAGM+S without marrow evidence of AML. Doses were escalated up to dose level six if \<2/6 patients out of each cohort of 6 had a DLT (some cohorts were expanded to 12 patients while awaiting completion of DLT monitoring period). The dose level at which dose escalation was stopped was the recommended phase 2 dose (RP2D).
Time frame: First 28 days of treatment
Phase 1: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of Sorafenib
MTD/RP2D will be defined as the highest dose studied in which the incidence of dose-limiting toxicity (DLT) is \< 33% assuming at least 6 patients have been treated at this dose. DLTs were defined as: 1) grade ≥3 non-hematologic toxicity lasting \>48 hours leading to \>7-day delay of the next cycle; 2) grade ≥4 non-hematologic toxicity if no recovery to grade ≤2 in 14 days (both excluding febrile neutropenia/ infection); 3) Absolute neutrophil count \<500/ µL or platelet count \<50,000/µL for \>49 days after CLAGM+S without marrow evidence of AML. Doses were escalated up to dose level six if \<2/6 patients out of each cohort of 6 had a DLT (some cohorts were expanded to 12 patients while awaiting completion of DLT monitoring period). The dose level at which dose escalation was stopped was the recommended phase 2 dose (RP2D).
Time frame: First 28 days of treatment
Phase I and II: Rate of Minimal Residual Disease Negative (MRDneg) Complete Response (CR)
We will determine if the addition of sorafenib to CLAG-M improves the rate of MRDneg CR compared to our institution's historical control of CLAG-M alone in adults with newly-diagnosed AML/high-risk MDS.
Time frame: 56 days (2 cycles of induction chemotherapy)
Complete Remission (CR)
Complete remission (CR) is defined as bone marrow blasts \<5%; absence of circulating blasts; absence of extramedullary disease; ANC ≥1.0 x 10\^9/L; platelet count ≥100 x 10\^9/L. CR with incomplete hematologic recovery (CRi) is CR with ANC \<1.0 x10\^9/L or platelet count \<100 x 10\^9/L. Measurable residual disease (MRD) is assessed by multiparameter flow cytometry and PCR. Morphologic leukemia free state (MLFS) is bone marrow blasts \<5%; absence of circulating blasts; absence of extramedullary disease; no hematologic recovery. Resistant disease is defined as not not meeting the criteria for CR, CRi, MLFS.
Time frame: Up to 5 years
Overall Response Rate (ORR)
ORR, defined as CR+CRi, rates of patients treated with CLAG-M with sorafenib.
Time frame: Up to 5 years
Overall Survival (OS)
12-month overall survival
Time frame: 12 months
Event-free Survival (EFS)
12-month event free survival
Time frame: 12 months
Relapse-free Survival (RFS)
12-month relapse free survival (RFS)
Time frame: 12 months
Number of Participants With Adverse Events
Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Time frame: Up to 5 years
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